Modeling The Two-hit Hypothesis Of Schizophrenia: Combined Neonatal Stress And Postnatal Corticosterone In Rats
Funder
National Health and Medical Research Council
Funding Amount
$318,500.00
Summary
Schizophrenia is a severe mental illness defined by a number of symptoms including hallucinations, delusions, social withdrawal and cognitive impairment. Factors very early in development have been suggested to induce an increased vulnerability to this illness. Recently, it was suggested that another major event, later in life, would be needed before vulnerable individuals would develop schizophrenia. The aim of this project is to model this two-hit hypothesis in rats. We will compare the effect ....Schizophrenia is a severe mental illness defined by a number of symptoms including hallucinations, delusions, social withdrawal and cognitive impairment. Factors very early in development have been suggested to induce an increased vulnerability to this illness. Recently, it was suggested that another major event, later in life, would be needed before vulnerable individuals would develop schizophrenia. The aim of this project is to model this two-hit hypothesis in rats. We will compare the effect of various neonatal maternal separation protocols as an early stressful event, followed by chronic treatment with the stress hormone corticosterone at various stages later in life. We will also perform a detailed anatomical study of the hippocampus of these rats. This brain area has been implicated in the development of schizophrenia in humans. We will also investigate if treatment with antipsychotic drugs can prevent or reverse behavioural and neuroanatomical changes seen in the rats. This will be the first comprehensive study to model this two-hit neurodevelopment hypothesis of schizophrenia and will provide an experimental verification of a clinical concept which is very difficult to prove in patients.Read moreRead less
Relationship Between Anterior Cingulate Morphology, Neuronal Integrity And Function In Schizophrenia And OCD
Funder
National Health and Medical Research Council
Funding Amount
$312,813.00
Summary
Schizophrenia and obsessive-compulsive disorder (OCD) are extremely disabling psychiatric disorders. Both tend to appear in early adulthood and have a number of important similarities. These include problems with planning and organising thoughts, abnormal brain chemistry, and changed function in the same brain region, the anterior cingulate. The anterior cingulate has been known for some time to be involved in emotion, motivation and attention. However, it is now recognised as the interface betw ....Schizophrenia and obsessive-compulsive disorder (OCD) are extremely disabling psychiatric disorders. Both tend to appear in early adulthood and have a number of important similarities. These include problems with planning and organising thoughts, abnormal brain chemistry, and changed function in the same brain region, the anterior cingulate. The anterior cingulate has been known for some time to be involved in emotion, motivation and attention. However, it is now recognised as the interface between the emotional, feeling part of the brain and the controlling, thinking part. Many, if not all, of the functions performed by the anterior cingulate are disturbed in both schizophrenia and OCD, meaning that studying this region may provide important clues to the nature of the two illnesses. One important characteristic of the anterior cingulate which has not been considered in previous research is its division into three distinct subregions, each with their own specific function. In particular, there is a cognitive region, which deals with response selection and information processing, and an emotional region, which assesses motivational content and controls emotional learning. Because of the nature of the two disorders we intend to study, we believe that schizophrenia will be associated with more abnormalities of the cognitive region, while OCD will be associated with changes in the emotional region. Another important feature of our research design is that we intend to collect data from the same subjects using four separate brain imaging techniques, which provide information about different levels of brain structure and function. This will allow us to interpret our findings from measures of brain chemistry in the context of our findings of brain function. Hopefully this will help us to clarify the pathophysiology of schizophrenia and OCD, and provide potential ways to assess the effect of different treatment strategies in these illnesses.Read moreRead less
Cancer is still a major cause of mortality in adults and children. Several lines of evidence suggest that some childhood cancers may arise due to factors, which interfere with the normal process of early development in embryonal tissues. The nature of the molecular factors which derail normal embryogenesis, their mechanism and timing, is vital information for efforts to generate novel pharmaceuticals. Moreover, factors which are necessary for tumour initiation, might be very good targets for a c ....Cancer is still a major cause of mortality in adults and children. Several lines of evidence suggest that some childhood cancers may arise due to factors, which interfere with the normal process of early development in embryonal tissues. The nature of the molecular factors which derail normal embryogenesis, their mechanism and timing, is vital information for efforts to generate novel pharmaceuticals. Moreover, factors which are necessary for tumour initiation, might be very good targets for a cancer prevention strategy. If entirely successful, our experiments will show that the MYCN oncoprotein is a key factor in the very earliest stages of neuroblastoma tumour formation, we will define the mechanism of the MYCN effect on the normal process of neural crest development, and, we will provide a basis for future cancer prevention strategies in children with this disease.Read moreRead less
Studying The Two Hit Hypothesis Of Psychiatric Illness: Role Of Brain-derived Neurotrophic Factor (BDNF)
Funder
National Health and Medical Research Council
Funding Amount
$469,553.00
Summary
Early environmental factors may play an important role in the development of psychiatric illnesses, such as schizophrenia and depression. We will study an animal model which combines early developmental stress followed by treatment with a stress hormone or chronic cannabis use in adolescence. We will assess behavioural changes and the role of a growth factor in the brain, BDNF. This wil lead to a better understanding of the role of neurodevelopmental stress in psychiatric disease.
The Role Of The Gtf2i Gene Family In Behaviour And Williams Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$629,396.00
Summary
Williams Syndrome (WS) is a complex neurodevelopmental disorder in humans caused by a deletion of 21 genes on chromosome 7. This results in a reduced IQ and marked visuospatial deficiencies. However, unlike other forms of mental retardation, some important cognitive abilities are completely normal. WS patients show normal development of linguistic abilities and anecdotal evidence suggests they possess an above average musical ability. In addition, these individuals also possess a characteristic ....Williams Syndrome (WS) is a complex neurodevelopmental disorder in humans caused by a deletion of 21 genes on chromosome 7. This results in a reduced IQ and marked visuospatial deficiencies. However, unlike other forms of mental retardation, some important cognitive abilities are completely normal. WS patients show normal development of linguistic abilities and anecdotal evidence suggests they possess an above average musical ability. In addition, these individuals also possess a characteristic overfriendly, gregarious personality with little inhibition towards strangers. Such a characteristic cognitive and behavioral profile in a genetic disorder has provided convincing evidence that genes play a role in specifying cognitive abilities and behavior. This interesting syndrome gives us an insight into the perplexing debate of Nature vs Nurture. It also provides a unique and invaluable opportunity to dissect the role of certain genes in complex neurodevelopmental pathways that result in cognition and behavior. Recently, patients with smaller (atypical) deletions of genes in the WS region have been described. These patients do not display the full 'classical' range of WS characteristics. The identification of which genes are deleted in these patients suggests that two genes in particular, GTF2IRD1 and GTF2I, are involved in visuospatial abilities, sociability and specific anxieties and phobias. Our laboratory was the first to identify proteins encoded by GTF2IRD1, known as MusTRDs, that act for the most part to suppress gene expression. Furthermore, our laboratory has been studying a mouse model in which the Gtf2ird1 gene has been deleted, similar to the situation in WS, and have found that the mice are more 'social' and exploratory. In this project, we want to determine if other behavioural features of WS are contributed to by this gene and-or its related gene, Gtf2i, and to characterize the role that these genes play in neuronal cell function.Read moreRead less
Life Course Trajectories And Neuropsychiatric Outcomes In An E-cohort Of High Risk Children Of Mothers With Psychosis
Funder
National Health and Medical Research Council
Funding Amount
$796,484.00
Summary
This study investigates how genetic and environment factors operate over the life course to increase risk of adverse outcomes for children of women with severe mental illness. We examine the clustering of neuropsychiatric outcomes in families and individuals, the role of developmental adverse life events in the risk for these outcomes, and the children's physical morbidity and offending profiles. This is an electronic cohort (e-cohort), constructed by record linkage across many databases.